Clonal evolution is a potentially life threatening long-term complication of inherited and acquired bone marrow failure BMF disorders. Cytogenetic clonal abnormalities develop in approximately 10 percent of patients with acquired aplastic anemia. The risk of early progression to myelodysplastic syndrome MDS and leukemia is also markedly elevated in patients with inherited marrow failure syndromes compared to age-matched controls. Prognosis of different clonal abnormalities is variable. Somatically acquired clonal deletions of one copy of chromosome 7 monosomy 7 or part of the long arm of chromosome 7 del7q are generally associated with a poor prognosis. Deletions involving chromosome 7 are frequently associated with therapy-related MDS, hypocellular MDS, MDS arising in children, and in MDS arising in patients with marrow failure. The goal of this project is to model monosomy 7 arising in marrow failure by utilizing induced pluripotent stem cells iPSC derived from patients with the inherited marrow failureleukemia predisposition syndrome Shwachman-Diamond syndrome SDS into which a deletion of the MDS-associated region of 7q has been genomically engineered. We will perform functional genomic screens to identify genes and molecular pathways with synthetic lethality for the del7q clone. These studies will provide a platform for the development of new strategies to treat monosomy 7 clonal disease arising from marrow failure.